1Department of Genetic Medicine and Development, University Medical Center, University of Geneva, Geneva, Switzerland

2Department of Infectious Diseases and the Copenhagen Muscle Research Centre, The Centre of Inflammation and Metabolism, Rigshospitalet,
Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

4Division of Endocrinology, Diabetology and Metabolism, University Hospital, Basel, Switzerland

Corresponding author: Karim Bouzakri, karim.bouzakri{at}unige.ch.

Abstract

OBJECTIVE Type 2 diabetes is characterized by insulin resistance with a relative deficiency in insulin secretion. This study explored
the potential communication between insulin-resistant human skeletal muscle and primary (human and rat) β-cells.

RESEARCH DESIGN AND METHODS Human skeletal muscle cells were cultured for up to 24 h with tumor necrosis factor (TNF)-α to induce insulin resistance,
and mRNA expression for cytokines was analyzed and compared with controls (without TNF-α). Conditioned media were collected
and candidate cytokines were measured by antibody array. Human and rat primary β-cells were used to explore the impact of
exposure to conditioned media for 24 h on apoptosis, proliferation, short-term insulin secretion, and key signaling protein
phosphorylation and expression.

RESULTS Human myotubes express and release a different panel of myokines depending on their insulin sensitivity, with each panel
exerting differential effects on β-cells. Conditioned medium from control myotubes increased proliferation and glucose-stimulated
insulin secretion (GSIS) from primary β-cells, whereas conditioned medium from TNF-α–treated insulin-resistant myotubes (TMs)
exerted detrimental effects that were either independent (increased apoptosis and decreased proliferation) or dependent on
the presence of TNF-α in TM (blunted GSIS). Knockdown of β-cell mitogen-activated protein 4 kinase 4 prevented these effects.
Glucagon-like peptide 1 protected β-cells against decreased proliferation and apoptosis evoked by TMs, while interleukin-1
receptor antagonist only prevented the latter.

CONCLUSIONS Taken together, these data suggest a possible new route of communication between skeletal muscle and β-cells that is modulated
by insulin resistance and could contribute to normal β-cell functional mass in healthy subjects, as well as the decrease seen
in type 2 diabetes.